Childhood epilepsy in the setting of cortical dysplasia is unusually severe and generally resistant to medical management. Surgery to remove dysplastic seizure foci often decreases or eliminates seizure activity, suggesting that cortical dysplasia can cause epileptic activity. Little is known about the cause of pharmacologic resistance in these patients, and human studies of mechanisms of epileptogenesis and pharmacologic resistance are generally not possible and at best difficult to perform. Rats treated with methylazoxymethanol (MAM) during fetal development exhibit many features that are similar to human cortical dysplasia. MAM is a potent teratogenic and neurotoxic agent that disrupts CNS cell migration, resulting in microencephaly and consistent and reproducible malformations of neocortical and hippocampal architecture (heterotopia and lamination disturbances) similar to those seen in human brains. Furthermore, MAM-exposed rats are susceptible to the development of seizures in vivo when exposed to convulsants such as kainic acid, hyperthermia, or flurothyl. Finally, hippocampal slice preparations, which largely preserve neural circuitry, demonstrate enhanced seizure susceptibility and hyperexcitablility in vitro. We propose to use this model to characterize anticonvulsant drug effect on hyperexcitability in: 1) the live rat, 2) the hippocampal slice preparation, and 3) in single cell recordings in hippocampal neurons. Proposed drugs for study include the traditional anticonvulsants Dilantin and phenobarbital, as well as less studied agents such as erythromycin and chromakalim. These latter drugs have been shown to open calcium-activated K channels, which are thought to be defective in dysplastic brains. Our ultimate goal is the rational design of novel anticonvulsants.